Zhang Meng, Liu Yi, Chen Jing, Chen Lei, Zhang Li, Chen Xianguo, Hao Zongyao, Liang Chaozhao
Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.
Institute of Urology, Anhui Medical University, Hefei, 230022, Anhui, People's Republic of China.
J Inflamm Res. 2022 Apr 21;15:2551-2566. doi: 10.2147/JIR.S352336. eCollection 2022.
Chronic nonbacterial prostatitis (CNP) has a high incidence, low cure rate, and unclear pathogenesis. Here, we aimed to systematically identify effective diagnostic and therapeutic targets for CNP.
Prostate tissues were obtained from established mouse models and negative controls and were used for mRNA array sequencing and immunohistochemistry (IHC) staining. Predominant pathways were identified based on pathway enrichment analysis and pharmaceutical experiments. We also investigated the functional role of CXCL12 on CP, a critical factor belonging to the predominant chemotaxis pathway, and employed IHC staining to explore the influence of the CXCL12/CXCR4 axis on the activation of the NF-κB, AKT, and STAT3 signaling pathways. Serum samples derived from both CNP cases and healthy controls were used to determine the secretion level of CXCL12.
By employing mRNA array sequencing and immunohistochemistry, we found that CXCR4, CXCL12, CD44, and OFLM4 were highly expressed in the infiltrated inflammatory T cells of the prostate tissues generated from CNP mice, while they were rarely expressed on the epithelial cells. Based on the pathway enrichment results, we applied pathway inhibitors to suppress the activity of these classic pathways. We found that targeting the CXCL12/CXCR4 axis with its specific antagonist AMD3100 remarkably alleviated inflammatory infiltration of the prostate in CNP models. Similar results were obtained when we replaced AMD3100 with adenovirus-associated virus (AAV)-sh. To clarify the potential mechanisms of how the CXCL12/CXCR4 axis influences the pathogenesis of CNP, we tested the classical downstream pathways. The results suggested that p-Akt, p-STAT3, and p-NF-κB were more highly expressed on the inflammatory cells of the prostate derived from the CNP model and were partly suppressed after applying AMD3100 or delivering AAV-sh, indicating that the CXCL12/CXCR4 axis potentially functioned through AKT/NF-κB and STAT3 signaling to influence the pathogenesis of CNP.
Our study provides potential diagnostic biomarkers and therapeutic targets for CNP.
慢性非细菌性前列腺炎（CNP）发病率高、治愈率低且发病机制不明。在此，我们旨在系统地确定CNP的有效诊断和治疗靶点。
从已建立的小鼠模型和阴性对照中获取前列腺组织，用于mRNA阵列测序和免疫组织化学（IHC）染色。基于通路富集分析和药物实验确定主要通路。我们还研究了CXCL12对CP的功能作用，CP是主要趋化通路中的一个关键因子，并采用IHC染色来探究CXCL12/CXCR4轴对NF-κB、AKT和STAT3信号通路激活的影响。使用来自CNP病例和健康对照的血清样本测定CXCL12的分泌水平。
通过mRNA阵列测序和免疫组织化学，我们发现CXCR4、CXCL12、CD44和OFLM4在CNP小鼠产生的前列腺组织浸润性炎性T细胞中高表达，而在上皮细胞上很少表达。基于通路富集结果，我们应用通路抑制剂来抑制这些经典通路的活性。我们发现用其特异性拮抗剂AMD3100靶向CXCL12/CXCR4轴可显著减轻CNP模型中前列腺的炎性浸润。当我们用腺相关病毒（AAV）-sh替代AMD3100时也得到了类似结果。为阐明CXCL12/CXCR4轴影响CNP发病机制的潜在机制，我们测试了经典下游通路。结果表明，p-Akt、p-STAT3和p-NF-κB在CNP模型来源的前列腺炎性细胞上表达更高，在应用AMD3100或递送AAV-sh后部分受到抑制，表明CXCL12/CXCR4轴可能通过AKT/NF-κB和STAT3信号发挥作用以影响CNP的发病机制。
我们的研究为CNP提供了潜在的诊断生物标志物和治疗靶点。
